In the anterior pituitary, the gonadotroph synthesizes luteinizing hormone (LH) and follicle stimulating hormone (FSH), which are critical for normal reproductive function. Recent evidence indicates that the gonadotroph develops from a pituitary progenitor cell by acquisition of GATA2 expression. Subsequently, gonadotrophs synthesize and secrete LH and FSH in response to gonadotropin-releasing hormone (GnRH). GnRH bound to its receptor activates several intracellular signaling pathways shared with insulin and insulin like growth factor 1 ([GF-1). Importantly, GnRH signaling activates an activating protein 1 (AP-1) element in the 5' flanking region of the GnRH receptor (GnRHr) gene, leading to increased GnRHr density on gonadotrophs. Both GATA factors and AP-1 recruit CREB (cAMP response element binding protein) binding protein (CBP) to the transcription complex, where it functions as a potent co-activator. My laboratory has recently identified a phosphorylation site on CBP which is a potential target for both GnRH and insulin signaling pathways. Since insulin signaling is clearly essential for the response of the reproductive axis to nutritional stimuli, its role and interaction with GnRH signaling in the gonadotroph will be explored. Therefore, the goals of this project will be to determine the importance of the pituitary gonadotroph in insulin regulation of the reproductive axis, and the molecular mechanism whereby insulin regulates gonadotroph-specific gene expression. Three specific aims are proposed. In aim 1, the specific role of insulin signaling in the gonadotroph will be determined using a conditional knock out (cKO) of the insulin receptor in the [gonadotroph.] In aim 2, the molecular mechanism(s) of CBP interaction(s) with gonadotroph-speciflc transcription factors, such as AP-1 and Egr-1, will be explored. Finally in Aim 3, the importance of CBP in the gonadotroph will be definitively established through a cKO of this co-activator. These studies will lead to unique insights into mechanisms responsible for insulin and GnRH regulation of gonadotropin secretion in the pituitary.